Over the last few years, there has been a growing trend of combining immune checkpoint inhibitors with additional mechanisms of action (MoAs) in oncology. Currently, the only pharmaceutical class close to delivering on the promise of ushering the next fundamental breakthrough in this area is the class of indoleamine-pyrrole 2,3-dioxygenase (Ido ) inhibitors.
Much hinges on the mid-year readout from the pivotal Phase III KEYNOTE-252/ECHO-301 trial, which is testing Incyte ’s epacadostat, an oral small molecule inhibitor and first-in-class IDO. The trial will assess epacadostat’s efficacy in combination with Merck & Co’s anti-programmed cell death protein 1 (anti-PD-1), Keytruda (pembrolizumab), in melanoma patients naïve to both PD-1 and programmed death-ligand 1 (PD-L1) inhibitors. This first, crucial readout for the closely-watched IDO class will address questions regarding whether the substantial hype behind this class is justifiable. Moreover, it will provide a strong indication as to whether the glut of IDO combinations in clinical testing—with assets from players such as Bristol-Myers Squibb , Roche , AstraZeneca , Pfizer , and Newlink—is a viable strategy. Success in this trial will undeniably afford the combination with the momentum required to challenge the standard of care in melanoma with immuno-oncology monotherapies.
Adding IDO inhibition
IDO is an immunomodulatory enzyme that breaks down the essential amino acid tryptophan, which in turn contributes to an immunosuppressive microenvironment within tumours via different mechanisms. Pharmacological inhibition of the IDO pathway produces immuno-activating and anti-neoplastic activities; namely, reinstating the proliferation and activation of tumour-eliminating immune cells, reducing the expansion of tumour-promoting immune cells, and offsetting the immunosuppressive effects of tryptophan metabolites. Adding IDO inhibition to immune checkpoint blockade by combining with the currently-approved mechanisms of action, cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and PD-1/PD-L1, is particularly attractive because IDO inhibitors elicit synergistic changes to the tumour microenvironment through mechanisms that are not directly targeted by current immunotherapies.
Although there is considerable excitement over IDO inhibitors, there are currently no data available in a large cohort of patients for any indication. This makes the results from the ECHO-301 trial a key point in validating whether IDO inhibition enhances the efficacy of an anti-PD-1, such as Keytruda. The key outcome for the Echo-301 read will be median progression-free survival. The other co-primary endpoint, median overall survival, requires more time to reach maturity, and statistical significance may not be reached by the expected release of the sponsor-unblinded data.
Superior median PFS?
Cross-trial comparative data in first-line advanced melanoma indicates that Keytruda + epacadostat has the potential to achieve superior median PFS to reported median PFS values. For reference, in Merck & Co’s KEYNOTE-006 trial, Keytruda monotherapy achieved a PFS of 5.6 months at the optimal dose, and in Bristol-Myers Squibb’s Checkmate 067 trial, Opdivo (nivolumab) monotherapy reached a PFS of 6.9 months while Opdivo + Yervoy (ipilimumab) reached a PFS of 11.7 months. The Opdivo + Yervoy combination is beset by high rates of adverse effects; thus, if epacadostat can provide a comparable survival benefit to PD-1 + CTLA-4 inhibition, Incyte can proclaim a victory in this space. Moreover, early trials with epacadostat have shown a promising safety profile, which could prove an incisive differentiating factor against Opdivo + Yervoy, as has already been noted by key opinion leaders (KOLs).
Hints that epacadostat provides superior efficacy and safety have come from Incyte unveiling the data from the ongoing, uncontrolled, Phase I/II KEYNOTE-037/ECHO-202 trial in advanced melanoma at the European Society for Medical Oncology (ESMO) 2017 Congress. Interim efficacy data of the Keytruda + epacadostat combination demonstrated an impressive PFS of 12.4 months for all comers regardless of therapy line, and a staggering PFS of 22.8 months for first-line advanced patients. In comparison, Opdivo + Yervoy reached a PFS of 11.7 months in the Checkmate 067 trial, at the cost of severe adverse events. Although the magnitude of survival benefit is expected to decrease with a longer follow-up and results from a blinded study will be inferior to those of an uncontrolled study, the outlook for epacadostat looks favourable so far.
Beyond the impact this trial will have on IDO and immunotherapy combinations in oncology, it will also influence a number of less of auspicious matters. Questions are likely to arise, including whether melanoma patients naïve to checkpoint blockade are the best patient group to target, whether the tryptophan metabolism pathway is druggable, and whether strategies involving IDO inhibition with immune checkpoint blockade will pay dividends in settings outside melanoma. Multiple projects are ongoing in settings such as non-small cell lung cancer and head and neck squamous cell carcinoma. As the onrush of substantial investment and exclusive deals in the IDO inhibitor sector surges, this readout will gauge the potential for epacadostat’s market share in melanoma and calibrate expectations for the IDO inhibitor class as a whole.
GlobalData (2017). Expert Insight: ESMO 2017: Promising Melanoma Data for the Keytruda plus Epacadostat Combo Resonate Emphatically, September 2017, GDHC1344EI
GlobalData (2017). PharmaPoint: Melanoma – Global Drug Forecast and Market Analysis to 2026, September 2017, GDHC159PIDR
GlobalData (2017). Non-Small Cell Lung Cancer (NSCLC) – Dynamic Market Forecast to 2025, August 2017, GDHC001FS
Upcoming Related Reports
GlobalData (2018). Melanoma: Dynamic Market Forecast to 2027, to be published
GlobalData (2018). Head and Neck Squamous Cell Carcinoma – Opportunity Analysis and Forecast to 2026, to be published